A series of structurally diverse 4-bromo spiro-isoxazolines possessing a variety of aromatic and aliphatic substituents at the 3 position, were synthesized through a 1,3-dipolar cycloaddition followed by intramolecular cyclization of a pendant hydroxyl or carboxylic acid group. The biochemical antiproliferative activity was evaluated in vitro by using two breast cancer cell lines (MCF-7 and MDA-MB-231) and two prostate cancer cell lines (PC-3 and DU-145) using the MTT viability assay, and the IC50 values were obtained. Spiro-isoxazoline derivatives bearing a p-chloro or an o-dichloro aromatic substituent at the 3-position of the isoxazoline showed considerable antitumor activities in all four cell lines with IC50 value ranging from 43μM to 56μM.

Duryne is a C30 polyacetylenic alcohol with C2 symmetry. Despite its potent cytotoxicity, its central double bond geometry and the absolute configuration of the chiral centers were not determined. We report the total syntheses of both enantiomers of the anticancer natural product (+)-duryne and the establishment of its stereochemistry by synthesizing both geometric isomers. The natural (+)-duryne is identified as (15Z) and (3S,28S) as shown in structure 1. The autoxidation/Wittig coupling reaction was employed to synthesize the central (Z)-olefin. The stereochemistry of the (E)-alkene isomer was constructed stereoselectively by using LiAlH4 reduction of the corresponding alkyne. The absolute configurations of the chiral centers are established by using Burgess' enzymatic resolution procedure with Pseudomonas AK lipase.

The stereoselective synthesis of 4-bromo-spiro-isoxazolines was achieved in one step through the bromination of various isoxazoles that contain a pendant alcohol or carboxylic acid functional group. Isoxazole bromination leads to a bromonium ion intermediate which opens either by neighboring oxygen lone pair electrons or by intramolecular nucleophilic attack. Single X-ray crystal data provides evidence that the two contiguous stereocenters of the spiro-isoxazoline are formed by the anti intramolecular attack of the nucleophile relative to bromine since there is an anti stereochemical relationship between the spirocyclic ring oxygen and the bromine atom. KeywordsIntramolecular Cyclization; Cycloaddition; Stereoselectivity; Regioselectivity; Heterocycles; Spirocycles Spiro-isoxazolines are found in a number of natural products, 1 and due to their biological activity,1a,1c-f ,2 many compounds within the psammaplysin and ceratinamide families have the potential to serve as a structural template that could lead to synthetic analogues that target a variety of diseases. The spiro-isoxazoline ring core is the central structural feature within the aforementioned natural products, and only a few publications address the synthesis of this unique ring system. 3,4 In the psammaplysin natural products, the oxepine oxygen and the 4-hydroxy group on the isoxazoline are anti to each other. A synthetic methodology that provides a stereoselective construction of spiro-isoxazolines that mimic the stereochemical features of the psammaplysin natural product is warranted. Herein we report the application of an oxonium mediated stereoselective intramolecular cyclization of a brominated isoxazole intermediate by a pendant alkoxide or carboxylate ion.Since the spiro-isoxazoline of the psammaplysin family of natural products contains an isoxazoline ring that has a substituent on the 4-position, the exploration of the possibility of reacting an isoxazole possessing a pendant nucleophilic functional group with an electrophile was performed in order to determine if an intramolecular cyclization would take place. 5 Our retrosynthetic rationale is depicted in Scheme 1. *Corresponding author: Fax: +601 979 3674; e-mail: ashton.t.hamme@jsums.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn order to test our hypothesis, alkyne 1 was reacted with the nitrile oxide that was generated in situ from the base promoted reaction of α-chlorobenzaldoxime with triethyl amine to afford isoxazole 6 (3) regioselect...

Dideoxypetrosynol A is a C30 polyacetylenic alcohol with C2 symmetry. The first total synthesis of both enantiomers of the potent anti-cancer natural product (+)- and (−)-dideoxypetrosynol A is reported. The key step is an oxidative coupling of a homopropargyl phosphonium ylide to prepare the “skipped” (Z)-enediyne moiety. The natural dideoxypetrosynol A was isolated as a racemic mixture as shown in structure 1. The absolute configurations of the chiral centers are established for the (+)- and (−)-enantiomers using Burgess’ enzymatic resolution procedure with Pseudomonas AK lipase.

A concise synthesis of the natural polyenyne R-(−)-cicutoxin (1) is described. After several trials, the successful synthesis commenced with three key fragments, R-(−)-1-hexyn-3-ol (8), 1,4-diiodo-1,3-butadiene (9), and the THP protected 4,6-heptadiyn-1-ol (6). Sonogashira coupling of compound 9 with acetylenes 6 and 8 gave the 17-carbon frame, which upon regio-selective reduction of a triple bond with red Al and removal of the THP protecting group afforded the natural product in four linear steps. The triply convergent synthesis gave R-(−)-cicutoxin in 18% overall yield.